The mosquito Aedes aegypti is the primary urban vector of the viruses causing dengue and chikungunya fever for which vaccines and effective pharmaceuticals are lacking. Epidemic dengue is emerging in the Americas: Mexico has reported >750,000 clinical dengue cases since 2009. Endemic chikungunya fever was reported in the Americas for the first time in 2013 and is now spreading into the Caribbean and Mexico. The only available strategy to suppress dengue or chikungunya fever outbreaks is to reduce vector populations through insecticide applications. However, Ae. aegypti suppression is compromised through a recent rapid rise across Latin America of knockdown resistance (kdr) to pyrethroid insecticides. Widespread, heavy use of pyrethroid space sprays ? due to their strong human safety profile ? has created immense selection pressure for resistance. This resistance is primarily under the control of the voltage gated sodium channel gene (para). Our preliminary data show that high frequencies (>80%) of kdr-conferring alleles occur commonly in Ae. aegypti in Mexico, and that state-of-the-art netting treated with a synergized pyrethroid effectively kills susceptible Ae. aegypti but has unacceptably low (~20%) killing efficacy for Mexican Ae. aegypti strains with high frequencies of kdr-conferring alleles. Our preliminary studies also show that: a) even in the absence of gene flow barriers, local insecticide pressure, rather than migration of mosquitoes with kdr-conferring mutations, is the primary determinant of the local kdr profile for Ae. aegypti; and b) the frequency of kdr-conferring mutations in a highly resistant strain reverted from near fixation to lower levels within 14 generations when pyrethroid pressure was removed. These findings provide hope that the current, disastrous kdr situation can be reversed through insecticide resistance management (IRM) schemes to restore and protect the invaluable pyrethroid susceptibility resource in Ae. aegypti. The goals for this proposal are to demonstrate that pyrethroid susceptibility can be restored and protected in Ae. aegypti and Ae. albopictus through insecticide rotation and focused indoor spraying. We also will identify genes other than para that confer pyrethroid resistance in Ae. aegypti through RNAseq and deep sequencing of exon enriched libraries. Our partnering Mexican institution is Instituto Nacional de Salud Pblica ? Centro Regional de Investigacin en Salud Pblica (INSP-CRISP) in Tapachula.